KR20020050135A - Compositions for prevention and alleviation of skin wrinkles - Google Patents

Abstract

PURPOSE: Provided is an external use skin composition for preventing and smoothing skin aging such as skin wrinkles, by addition of compounds which accelerate collagen synthesis to the usual skin composition. CONSTITUTION: The composition comprises of adding one or more than two compounds of accelerator of collagen synthesis, selected from phenytoin, valproic acid, cyclosporin A, nifedipine, diltiazem, verapamil HCl and amoldipine. The above compounds are used in the amount of 0.000001-30wt.% based on the whole weight of the composition and the final composition is in the form of ointment, cream, lotion, toilet water, pack, patching agent and patch having fine needles.

Description

Composition for external use for skin wrinkle prevention and alleviation {Compositions for prevention and alleviation of skin wrinkles}

The present invention is a phenytoin (Vhenproto), Valproic acid (Valproic) having a collagen synthesis promoting effect on conventional ingredients such as creams, ointments, lotions, skins, gels, packs, patches, patch-type administration device for the skin absorption skin) containing one or more selected from the group consisting of acid, cyclosporin A, nifedipine, dildizem, diltiazem, verapamil HCl and amoldipine as active ingredients It relates to an external composition for skin for prevention and alleviation.

The causes of skin aging can be largely classified into internal factors such as aging and environmental factors. Depending on the area, there are neck wrinkles, forehead wrinkles, brow wrinkles, fine lines of eyes, fine lines under eyes, nasolabial folds, fine lines around the lips, and fine wrinkles on the entire face. Although there are individual differences in the appearance of wrinkles due to aging, in general, as age increases around the early 20s, the amount of collagen in the dermis of the skin decreases and elastic fibers change, resulting in fine wrinkles due to skin relaxation. . Collagen is a major matrix protein produced by skin fibroblasts and is present in extracellular epilepsy and is an important protein that accounts for 30% of the total weight of biological proteins. The main functions are known as mechanical firmness of skin, resistance of connective tissue and binding of tissue, support of cell adhesion, induction of cell division and differentiation. Such collagen is also destroyed by exposure to ultraviolet light, which is an external cause of skin aging, and the change by ultraviolet light is known to be proportional to the accumulation of time exposed to ultraviolet light. Ultraviolet rays accumulate elastic fibrous material in the dermis of the skin and denature collagen fibers, causing wrinkles on the skin and reducing elasticity. Other environmental factors, such as wind, heat and tobacco, are known to promote skin aging.

As such, collagen, which is closely related to skin aging, decreases due to aging and light aging due to UV irradiation, and is generally reduced by about 65% compared to 20 years of age at 80 years of age, which not only causes skin thinning but also It is known to be closely related to wrinkle formation.

As extensive research for the prevention and alleviation of such wrinkles has been developed, important functions of collagen in the skin have been revealed. From these studies, if collagen metabolism is activated by promoting the synthesis of collagen in the skin, the components of dermal matrix are increased to improve wrinkles, It has been found to have effects such as elasticity enhancement and skin tightening. There are products that combine collagen with cosmetics from the skin moisturizing effect of collagen, but these cosmetics are applied to the surface of the skin, and it is said that it is essential to improve skin function because it is difficult to absorb the percutaneous absorption of collagen, which is a polymer, Can not. Retinoic acid, trans-forming growth factor (TGF-β), protein from animal placenta (JP8-231370), betulinic acid (JP8-208424), chlorella extract (JP9-) 40523, JP10-36283) and the like, but retinoic acid is unstable and has limited use due to stability problems such as irritation and redness when applied to the skin. Chlorella extract and the like have little effect to substantially promote skin collagen synthesis. It is not possible to expect a functional improvement effect, but recently emerging wrinkle treatment methods include ultrasound treatment and skin scaling, laser dermabrasion, botulinum toxin injection, restile injection, etc., but they are not effective in terms of procedure cost and persistence. Therefore, there is an urgent need for development and discovery of a promoter having excellent collagen synthesis promoting effect in vivo.

Therefore, the present inventors conducted a study to find a compound having a collagen synthesis promoting effect, phenytoin (Vhenytoin), Valproic acid (cycloproic acid), cyclosporin A which is used as an existing anticonvulsant, immunosuppressant, calcium channel inhibitor (Cyclosporin A), nifedipine (Nifedipine), diltiazem, Verapamil HCl, and Amoldipine showed very strong collagen synthesis promoting effects in human-derived fibroblasts. When applied to the skin of the skin was confirmed to be excellent in the generation and suppression of wrinkles, the present invention was completed by revealing the excellent effect on the inhibition and prevention of skin aging, such as wrinkles.

Phenytoin and Valproic acid, which are the active ingredients of the present invention, are widely used as anticonvulsants for inhibiting convulsions in epilepsy and have been reported for collagen synthesis (USP5686489, Minerva Stomatol). 1998 Sep; 47 (9): 387-98). Cyclosporin A is an immunosuppressive agent that has already been widely used to suppress tissue rejection after organ transplantation and has been reported for collagen synthesis (J Periodontol 2001 Jul; 72 (7): 921-31). Nifedipine, Diltiazem, Verapamil HCl and Amoldipine are already used as calcium channel inhibitors, and there are reports of collagen synthesis (J Periodontol 2001 Aug; 72 (8)). : 1078-83, Proc Natl Acad Sci USA 1996 May 28; 93 (11): 5478-82, J Urol 1996 Dec; 156 (6): 2067-72). However, the use of the above drugs as external preparations for skin for preventing and alleviating skin wrinkles has not been reported.

Hereinafter, experimental examples and examples of the composition for external application of skin for the purpose of preventing and alleviating skin wrinkles of the present invention will be described in detail.

Experimental Example 1: Collagen production promoting effect of the present invention in fibroblasts

The active ingredient of the present invention was added to the culture of human-derived fibroblasts to test the effect of promoting collagen synthesis at the cellular level. The biosynthetic collagen was measured by applying the method of Martens, Gut 1992, 33, 1664-1670, and the collagen biosynthesis promoting effect was measured. The results are summarized in Table 1 with 100% of no sample added. Detailed experimental method is as follows.

Human-derived fibroblasts were dispensed into 24 well plates for cell culture, incubated for 24 hours under 10% Fetal Bovine Serum (FBS), and washed twice with PBS (Phosphate Buffered Saline). Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, and diltiazem at a final concentration of 10 ^-8 to 10 ^-5 M in medium containing 1% FBS Diltiazem), Verapamil hydrochloride (Verapamil HCl) and Amoldipine were added for 24 hours, followed by incubation. After the incubation, the cells and the culture medium were divided into two and a half, respectively, and collagenase was treated in only one fraction, followed by precipitating the protein with TCA (Trichloroacetic acid) to measure collagen biosynthesis promoting effect from the difference in radioactivity of the two fractions. The results are shown in Table 1 with 100% of no sample added.

Collagen Production Promoting Effect in Fibroblasts Compound concentration Control group 1 Test group 1 Test group 2 Test group 3 Test group 4 - 10 ^-8 M 10 ^-7 M 10 ^-6 M 10 ^-5 M Phenytoin 100.00 215.28 ^* 298.35 360.65 381.54 Valproic acid 100.00 201.13 283.24 332.11 370.21 Cyclosporin A 100.00 212.11 293.21 352.31 372.27 Nifedipine 100.00 204.31 292.21 330.30 358.16 Diltiazem 100.00 199.15 276.25 321.23 362.12 Verapamil HCl 100.00 183.25 280.23 331.09 355.12 Amoldipine 100.00 182.42 280.07 330.42 355.26

As can be seen from the results of Table 1, the collagen production promoting effect by the active ingredients of the present invention is a concentration-dependent collagen synthesis from 182.42% up to 381.54% as the concentration increases compared to the control group without addition of the compound The increase in collagen synthesis in fibroblasts was found to be very good.

Experimental Example 2 Evaluation of Promoting Collagen Production in Rat Skin

Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, Diltiazem, Verapamil HCl, the active ingredient of the present invention in animal skin In order to evaluate collagen production promotion by the application of Amoldipine, the method of Mard L DaCosta et al . (Surgery 1998, 123: 287-293) was evaluated.

In brief, five-week-old male SD rats were divided into five rats per test group, and a 1 cm incision was made at the center of the distribution. Then, 100 mg of PVA sponge (Unipoint Ind.) Was inserted and sutured, and 200 μl of each test substance was applied for 10 days. . At necropsy, the PVA sponge was used to quantify hydroxyproline. The extracted PVA sponge was placed in 4 ml of 6N HCl, hydrolyzed at 130 ° C. for 3 hours, completely dried, and incubated at 110 ° C. until 50 μl of methanol was removed to remove remaining hydrochloric acid. 1.2 ml of 50% isopropanol was added to dissolve the remaining precipitate and mixed with 200 μl of chloramine-T (Sodium p-toluensulfochloramide trihydrate) solution for 10 minutes. 1.2 ml of Ehrlich reaction reagent was added and incubated at 50 ° C. for 90 minutes, cooled at room temperature, and absorbance was measured at 558 nm. To prepare a standard solution of hydroxyproline, 1 mg of hydroxy proline was dissolved in 1 ml HCl, diluted to 0, 0.2, 0.4, 0.8, 1 mg / 25 μl 6N HCl, and hydrolyzed at 130 ° C. for 3 hours. The hydroxyproline levels quantified in each PVA sponge are shown in Table 2 as the percentage increase relative to hydroxyproline (100%) of the control group applied solvent only.

Evaluation of Collagen Production in Animal Skin Compound concentration Control group 1 Test group 1 Test group 2 Test group 3 Test group 4 - 10 ^-8 M 10 ^-7 M 10 ^-6 M 10 ^-5 M Phenytoin 100.00 132.58 ^* 143.51 167.41 182.47 Valproic acid 100.00 128.05 139.24 157.72 178.13 Cyclosporin A 100.00 131.02 143.07 164.82 179.26 Nifedipine 100.00 129.92 142.41 161.43 185.88 Diltiazem 100.00 122.44 136.76 157.45 175.23 Verapamil HCl 100.00 135.63 147.39 167.06 183.32 Amoldipine 100.00 132.50 149.65 163.84 181.12

As shown in Table 2, Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, Diltiazem, Verapamil HCl, and Amoldipine, which are active ingredients of the present invention, at least 122.44% Increased up to 185.88%, strongly promoting collagen synthesis in the skin.

Experimental Example 3 Evaluation of the Anti-wrinkle Effect in Hairless Mice

Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, Diltiazem, Verapamil HCl, Amaldipine (Phenytoin) Amoldipine) was evaluated for the effect of inhibiting wrinkle formation in mice.

Hairless mice at 6 weeks of age were divided into 15 test groups and 3 control groups of 10 mice each to evaluate the anti-wrinkle effect of each compound. Each compound was applied at a concentration of 10 ⁻⁸ to 10 ⁻³ M and treated only with the solvent without adding the compound as a control. Detailed test methods are as follows. Hairless mice were irradiated with 2MED (2x Minimal Erythema Dose) for 12 weeks 3 days a week using a solar stimulator. Each compound application was applied 30 minutes before UV irradiation. After 30 minutes, twice a day 100μL treatment for 10 weeks to determine the degree of inhibition of wrinkle formation. Determination of the degree of wrinkle formation inhibition was visually determined by visual inspection and photographing of the sample treatment area, and the criterion was no inhibition (0 point), slightly compared to the treatment group of each compound compared with the untreated sample (0 point). The number of animals was determined in four stages: suppression (1 point), moderate suppression (2 points), and significant suppression (3 points), and are shown in Tables 3A to 3C.

Evaluation of Wrinkle Formation Inhibitory Effect of Compound 10 ^-8 M in Hairless Mice Test group compound Wrinkle suppression (mari) 0 points 1 point 2 points 3 points Test group 1 Phenytoin 0 ^* 0 2 8 Test group 2 Valproic acid 0 One One 8 Test group 3 Cyclosporin A 0 One 2 7 Test group 4 Nifedipine 0 2 3 5 Test group 5 Diltiazem 0 2 2 6 Test group 6 Verapamil HCl 0 One One 8 Test group 7 Amoldipine 0 One One 8 Control group 1 - 10 0 0 0

^{* Number of} animals

Evaluation of Wrinkle Formation Inhibitory Effect of Compound 10 ^-5 M in Hairless Mice Test group compound Wrinkle suppression (mari) 0 points 1 point 2 points 3 points Test group 1 Phenytoin 0 ^* 0 3 7 Test group 2 Valproic acid 0 One 2 7 Test group 3 Cyclosporin A 0 One 3 6 Test group 4 Nifedipine 0 2 3 5 Test group 5 Diltiazem 0 2 2 6 Test group 6 Verapamil HCl 0 One 2 7 Test group 7 Amoldipine 0 One 3 6 Control group 1 - 10 0 0 0

^{* Number of} animals

Evaluation of Wrinkle Formation Inhibitory Effect of Compound 10 ^-3 M in Hairless Mice Test group compound Wrinkle suppression (mari) 0 points 1 point 2 points 3 points Test group 1 Phenytoin 0 ^* 0 3 7 Test group 2 Valproic acid 0 0 2 8 Test group 3 Cyclosporin A 0 0 2 8 Test group 4 Nifedipine 0 2 3 5 Test group 5 Diltiazem 0 One 2 7 Test group 6 Verapamil HCl 0 0 One 9 Test group 7 Amoldipine 0 0 2 8 Control group 1 - 10 0 0 0

^{* Number of} animals

As can be seen from the results of Tables 3a to 3c, Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, Diltiazem, Verapamil HCl Inhibition of wrinkle formation in hairless mice by Amoldipine was shown to be moderately effective at inhibiting wrinkle formation at 80% or more.

Experimental Example 4: Evaluation of the wrinkle improvement effect in the hairless mouse

Compounds of the invention Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, and diltiazem for light-induced wrinkles using 6-week-old hairless mice Wrinkle improvement effect by (Diltiazem), Verapamil HCl, Amoldipine was tested.

The hairless mice were divided into 15 test groups and 3 control groups of 10 mice each to apply 10 ⁻⁸ to 10 ⁻³ M of each compound, and the test method was as follows. Compounds and controls treated with a solvent without wrinkles by irradiating hairless mice with 2MED (2x Minimal Erythema Dose) for 10 weeks 3 days a week using a solar stimulator and adding samples. The degree of improvement was qualitatively determined in the group treated with 100 μl twice a day for 6 weeks after dividing into the test group added. The determination of wrinkle improvement was visually judged by visual inspection and photographing the sample treatment area, and the criterion was no improvement (0 point) and slight improvement (1 point) compared with each compound treatment group and control group before the sample treatment. ), The number of animals was determined in four stages of moderate improvement (two points) and significant improvement (three points), and are shown in Tables 4a to 4c.

Evaluation of the Wrinkle Improvement Effect of Compound 10 ^-8 M in Hairless Mice Test group compound Wrinkle improvement (mari) 0 points 1 point 2 points 3 points Test group 1 Phenytoin 0 ^* One 2 7 Test group 2 Valproic acid 0 One 2 7 Test group 3 Cyclosporin A 0 2 3 5 Test group 4 Nifedipine 0 2 3 5 Test group 5 Diltiazem 0 One 2 7 Test group 6 Verapamil HCl 0 2 2 6 Test group 7 Amoldipine 0 One One 8 Control group 1 - 9 One 0 0

^{* Number of} animals

Evaluation of Wrinkle Improvement Effect of Compound 10 ^-5 M in Hairless Mice Test group compound Wrinkle improvement (mari) 0 points 1 point 2 points 3 points Test group 1 Phenytoin 0 ^* One 3 6 Test group 2 Valproic acid 0 One 2 7 Test group 3 Cyclosporin A 0 2 2 6 Test group 4 Nifedipine 0 2 2 6 Test group 5 Diltiazem 0 One 2 7 Test group 6 Verapamil HCl 0 2 One 7 Test group 7 Amoldipine 0 2 2 6 Control group 1 - 9 One 0 0

^{* Number of} animals

Evaluation of the Wrinkle Improvement Effect of Compound 10 ^-3 M in Hairless Mice Test group compound Wrinkle improvement (mari) 0 points 1 point 2 points 3 points Test group 1 Phenytoin 0 ^* 0 3 7 Test group 2 Valproic acid 0 0 2 8 Test group 3 Cyclosporin A 0 2 2 6 Test group 4 Nifedipine 0 2 2 6 Test group 5 Diltiazem 0 0 2 8 Test group 6 Verapamil HCl 0 One 2 7 Test group 7 Amoldipine 0 One 3 6 Control group 1 - 8 2 0 0

^{* Number of} animals

As can be seen from the results of Tables 4a to 4c, Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, Diltiazem, Verapamil HCl ), Amoldipine (Amoldipine) has been shown to show more than moderate moderate wrinkles at 80% or more for the wrinkles generated by the light of hairless mice.

As a result of evaluating collagen synthesis promoting effect in human-derived fibroblasts, rats, and mice using the compound of the present invention, phenytoin, Valproic acid, cyclosporin A, nifedipine (Nifedipine), diltiazem (Diltiazem), Verapamil hydrochloride (Verapamil HCl), Amoldipine (Amoldipine) was found to be very effective in promoting collagen synthesis at a concentration of 10 ^-8 ~ 10 ^-3 M.

The external composition for skin containing the compound of the present invention includes all formulations that can be applied to the skin such as creams, ointments, lotions, skins, gels, packs, patching agents, patch-type administration devices equipped with micro-injection needles, It also includes an aerosol type. The composition of the present invention was prepared in creams, ointments, and packs to evaluate the reduction rate of wrinkles in humans, which was evaluated to have an effect of significantly reducing the density of wrinkles.

Examples of the formulation of a patch-type administration device equipped with a cream, an ointment, a pack, an essence, a flexible lotion, a nutrient solution, a patch, and a micro injection needle containing the compound of the present invention are shown below.

Hereinafter, the present invention will be described based on Examples and Comparative Examples, but the technical scope of the present invention is not limited to these Examples.

Evaluation of skin aging inhibition and therapeutic effect evaluation by the composition containing the compound of the present invention

The external preparation for skin was prepared using the compounds according to the present invention and other auxiliary ingredients at the composition ratios shown in Tables 5 to 7 below. In the present invention, a patch-type administration device equipped with an external skin ointment, a cream, a pack, an essence, a flexible lotion, a nutrient solution, a patch, and a micro-injection needle was prepared. Although used, these examples are not intended to limit the formulation and active ingredients of the present invention.

Preparation of an external skin ointment containing the compound of the present invention (unit: weight%) ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Diethyl sebacate 8 8 8 8 8 Prepayment 5 5 5 5 5 Polyoxyethylene ^* 6 6 6 6 6 Sodium benzoate Quantity Quantity Quantity Quantity Quantity Phenytoin 0.00001 0.1 - - - Cyclosporin A - - 0.00001 0.1 - With petroleum jelly 100 100 100 100 100

^* Polyoxyethylene oleyl ether phosphate

Preparation of skin external cream containing a compound of the present invention (unit: weight%) ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Stearic acid 15.0 15.0 15.0 15.0 15.0 Cetanol 1.0 1.0 1.0 1.0 1.0 Potassium hydroxide 0.7 0.7 0.7 0.7 0.7 glycerin 5.0 5.0 5.0 5.0 5.0 Propylene glycol 3.0 3.0 3.0 3.0 3.0 antiseptic Quantity Quantity Quantity Quantity Quantity incense Quantity Quantity Quantity Quantity Quantity Phenytoin 0.0001 0.001 - - - Cyclosporin A - - 0.0001 0.001 - With purified water 100 100 100 100 100

Preparation of an external skin pack containing the compound of the present invention (unit: wt%) ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 glycerin 5.0 5.0 5.0 5.0 5.0 Propylene glycol 4.0 4.0 4.0 4.0 4.0 Polyvinyl alcohol 15.0 15.0 15.0 15.0 15.0 ethanol 8.0 8.0 8.0 8.0 8.0 Polyoxyethylene Oleethyl 1.0 1.0 1.0 1.0 1.0 Paraoxybenzoic Acid Methyl 0.2 0.2 0.2 0.2 0.2 incense Quantity Quantity Quantity Quantity Quantity Phenytoin 0.1 0.5 - - - Cyclosporin A - - 0.1 0.5 - With purified water 100 100 100 100 100

Preparation of Essence Containing Compound of the Invention (Unit: Weight%) ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Cyclomethicone 15.0 15.0 15.0 15.0 15.0 Caprylic Capric Triglyceride 3.0 3.0 3.0 3.0 3.0 Mineral oil 3.0 3.0 3.0 3.0 3.0 Beeswax 1.0 1.0 1.0 1.0 1.0 Cetyl Dimethicone Copolyol 3.0 3.0 3.0 3.0 3.0 glycerin 5.0 5.0 5.0 5.0 5.0 Magnesium sulfate 3.0 3.0 3.0 3.0 3.0 Paraoxybenzoic Acid Ester Quantity Quantity Quantity Quantity Quantity Phenytoin 0.01 0.05 - - - Cyclosporin A - - 0.01 0.05 - With purified water 100 100 100 100 100

Preparation of flexible lotion containing a compound of the present invention (unit: wt%) ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 glycerin 2.0 2.0 2.0 2.0 2.0 Hyaluronic acid 1.0 1.0 1.0 1.0 1.0 Polyoxyethylene oleyl ether 0.1 0.1 0.1 0.1 0.1 Polyoxyethylene Cured Pizza Horse Oil 0.1 0.1 0.1 0.1 0.1 Paraoxybenzoic Acid Ester Quantity Quantity Quantity Quantity Quantity Spices Quantity Quantity Quantity Quantity Quantity Pigment Quantity Quantity Quantity Quantity Quantity Phenytoin 0.0001 0.001 - - - Cyclosporin A - - 0.0001 0.001 - With purified water 100 100 100 100 100

Preparation of Nutrient Liquid Containing Compound of the Present Invention (Unit: Weight%) ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Cetanol 1.0 1.0 1.0 1.0 1.0 Beeswax 0.5 0.5 0.5 0.5 0.5 Vaseline 2.0 2.0 2.0 2.0 2.0 Squalane 6.0 6.0 6.0 6.0 6.0 ethanol 3.0 3.0 3.0 3.0 3.0 1,3-butylene glycol 4.0 4.0 4.0 4.0 4.0 Polysorbate 60 1.0 1.0 1.0 1.0 1.0 Solbitan Sesqui Olate 0.3 0.3 0.3 0.3 0.3 Carboxy Vinyl Polymer 0.3 0.3 0.3 0.3 0.3 Triethanolamine 0.3 0.3 0.3 0.3 0.3 Paraoxybenzoic Acid Ester Quantity Quantity Quantity Quantity Quantity Spices Quantity Quantity Quantity Quantity Quantity Pigment Quantity Quantity Quantity Quantity Quantity Phenytoin 0.0001 0.001 - - - Cyclosporin A - - 0.0001 0.001 - With purified water 100 100 100 100 100

Preparation of the patch containing the compound of this invention (unit: weight%) division ingredient Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Polymer Carboxymethylcellulose One One One One One Polyacrylic acid 2 2 2 2 2 Crosslinking agent Acetaldehyde 0.1 0.1 0.1 0.1 0.1 Humectant glycerin 30 30 30 30 30 Inorganic fillers kaoline 0.1 0.1 0.1 0.1 0.1 antiseptic Paraoxybenzoic Acid Methyl 0.1 0.1 0.1 0.1 0.1 Paraoxybenzoic acid propyl 0.05 0.05 0.05 0.05 0.05 Buffer Sodium monophosphate 0.1 0.1 0.1 0.1 0.1 Trisodium Phosphate 0.05 0.05 0.05 0.05 0.05 Active ingredient Phenytoin 0.01 0.05 - - - Cyclosporin A - - 0.01 0.05 - By adding purified water 100 100 100 100 100 Support Cotton cloth Cotton cloth Cotton cloth Cotton cloth Cotton cloth Release Film silicon silicon silicon silicon silicon

Finally, in the patch-type drug administration device equipped with a micro-injection needle used for attaching to the skin, the drug solvent reservoirs forming the main part of the patch body include phenytoin, valproic acid, and cyclosporin A. It is composed of a polymer support that supports the entire administration device while preventing the penetration of drugs such as nifedipine, diltiazem, verapamil HCl and amoldipine. Examples of the solvent include water, polyethylene glycol, transcutol or ethanol. Polymer materials that can be used for the polymer support include polyethylene, polypropylene, nonwoven fabric, cotton cloth, and the like. In the lower part of the reservoir, the above-mentioned drug is dispersed in powder form and the skin micro-injection needle support and the skin micro-injection support composed of a polymer gel such as cellulose-based, polypropylene, fluorocarbon, and polycarbonate exhibiting swelling behavior upon release of the solvent after skin adhesion. A device for transdermal administration of a drug, characterized in that it consists of a plurality of skin microinjection needles which are fixedly distributed vertically on the injection needle support body and come into contact with the skin. It is attached to 10 to 50 pieces per area (cm ² ) and has a passage through which the drug can pass, the diameter is 1 to 1000㎛, fixed to be 0.01 to 3mm in length outside the skin micro-injection needle support At the bottom, the body having a reservoir attached to the skin It consists of a adhesive layer to the poly and using acrylate or materials such as polybutene, and should not be free from the side effects of the skin and lowering the adhesion of a solvent or dissolved. Finally, the adhesive layer has a release paper that can be easily removed when used, which prevents the leakage of the drug and protects the adhesive. Hereinafter, the present invention will be described in detail, but the present invention is not limited by the examples.

Preparation of Patches Equipped with Microinjection Needles Containing Compounds of the Invention

Comparative Example 1

Comparative Example The matrix is obtained by applying 1 g of a 3% gelatin solution onto a skin microinjection needle having a vertically fixed skin microinjection needle (15 pieces / cm 3) and vacuum drying in a lyophilizer.

Example 1

The phenytoin-dispersed matrix is evenly dispersed by adding 0.001% of phenytoin in 1 g of 3% gelatin solution, and the mixed solution is spread on a skin microinjection needle having a vertically fixed skin microinjection needle (15 pcs / cm 3) and then in a freeze dryer. Vacuum drying yields a phenytoin matrix.

Example 2

The matrix in which the cyclosporin A is dispersed is evenly dispersed by adding 0.001% of cyclosporin A in 1 g of a 3% gelatin solution, and the mixed solution is placed on the skin microinjection needle having a vertically fixed skin microinjection needle (15 / cm 3). Vacuum drying in lyophilizer gives cyclosporin A matrix.

In each of the above Examples and Comparative Examples, the effect of improving wrinkles was performed in women aged 35 to 60 years as follows. 300 women aged 35 to 60 years were divided into 15 groups of 20 people, and each Example and Comparative Example were applied to the facial part twice a day for 3 months (released 30 minutes after application in the case of Table 7 pack prescription). After 3 months, the degree of wrinkle improvement was evaluated by subject's questionnaire and image analysis of wrinkles. The subject's questionnaire was divided into four stages of improvement, slight improvement, moderate improvement, and significant improvement as compared to before use regarding wrinkle improvement and elasticity enhancement, and the results are shown in Table 12. Image analysis of wrinkles was performed using Xantopren (Bayer) before the experiment was started, and a replica was taken from the same area immediately after the experiment was completed. The density of wrinkles was measured by analysis. The results of the measurement of wrinkle density by image analysis are shown in Table 13 as a reduction ratio against wrinkle density before use.

Wrinkle reduction rate evaluation (persons) No improvement Minor improvements Moderate improvement A significant improvement Ointment Example 1 1 ^* 3 4 13 Example 2 0 2 4 14 Example 3 0 4 7 9 Example 4 0 3 6 11 Comparative Example 1 17 3 0 0 cream Example 1 0 One 8 11 Example 2 0 One 6 13 Example 3 0 2 7 11 Example 4 0 3 7 10 Comparative Example 1 13 7 0 0 pack Example 1 0 0 9 11 Example 2 0 2 5 13 Example 3 0 3 4 14 Example 4 0 One 5 14 Comparative Example 1 15 5 0 0 essence Example 1 0 2 5 13 Example 2 0 0 5 15 Example 3 0 3 6 11 Example 4 0 One 7 12 Comparative Example 1 12 7 One 0 Flexible lotion Example 1 0 2 8 10 Example 2 0 One 7 12 Example 3 0 3 7 10 Example 4 0 4 5 11 Comparative Example 1 16 4 0 0 Nutrition Example 1 0 One 5 14 Example 2 0 0 5 15 Example 3 0 One 7 12 Example 4 0 2 7 11 Comparative Example 1 13 7 0 0 Patch Example 1 0 One 4 15 Example 2 0 0 4 16 Example 3 0 One 7 12 Example 4 0 One 9 10 Comparative Example 1 15 5 0 0 Patch with micro needle Example 1 0 One 4 15 Example 2 0 One 9 10 Comparative Example 1 15 5 0 0

^* Number of people

Result of evaluation of density of wrinkles Ointment cream pack essence Flexible lotion Nutrition Patch Example 1 45% 43% 40% 39% 44% 45% 46% Example 2 44% 41% 38% 37% 42% 43% 48% Example 3 50% 40% 41% 40% 48% 46% 45% Example 4 48% 50% 44% 39% 45% 42% 44% Comparative Example 1 98% 105% 94 %% 97% 99% 98% 96%

As can be seen in Table 12, it can be seen that when using the embodiments according to the present invention, the effect of improving wrinkles and enhancing skin elasticity is excellent. In particular, more than 80% of the subjects are able to recognize the effects of moderate or higher wrinkle improvement and elasticity improvement. As can be seen from Table 13, it can be seen that the density of the wrinkles is greatly reduced by 37 to 50% than before use when applying the embodiment to which the compounds according to the present invention are added. As a result of evaluation of the density of the wrinkles of the patch-type administration device equipped with the micro-injection needle, Example 1 (70%) and Example 2 (60%) were also superior to the comparative example (98%).

The results of these experiments are caused by internal or external factors when the compounds of the present invention are used as external preparations for the skin of patch-type administration devices equipped with creams, ointments, packs, essences, softening lotions, nutrients, patching agents, and micro needles. It has been shown that it can improve wrinkles very effectively.

The external composition of the present invention is a phenytoin (Phenytoin), Valproic acid (Cyclosporin A), Nifedipine (Difetiapine), Diltiazem, Verapamil hydrochloride showing a collagen synthesis promoting effect HCl), by adding one or two or more selected from Amoldipine (Amoldipine) as an active ingredient, there is an excellent effect on the inhibition, relief and prevention of skin aging, such as wrinkles.

Claims (3)

Phenytoin, Valproic acid, Cyclosporin A, Nifedipine, Diltiazem, Verapamil HCl, Amoldipine A skin external composition containing one or two or more selected from the above) as an active ingredient. The composition for external application of skin according to claim 1, comprising 0.00001 to 30.00% by weight of an active ingredient having a collagen synthesis promoting effect, based on the total weight of the composition. The composition for external application of skin according to claim 1 or 2, wherein the formulation of the composition is a patch-type administration device equipped with an ointment, cream, lotion, lotion, pack, patch or micro injection needle.